Abstract/Project Summary Chronic pain affects over 100 million Americans. Of the 9.4 million Americans who take opioids for chronic pain, 2.1 million are estimated by the NIH to be dependent on them and are in danger of turning to the black market. 4 of 5 heroin addicts say they come to the drug from prescription pain killers. Management of chronic pain has increasingly relied upon high-dose chronic opioid therapy, with this change paralleled by increasing numbers of individuals affected by opioid abuse, and dramatic rises in opioid-related overdose and death. Thus, it is imperative that we test and validate cost-effective, non-pharmacological interventions, such as Cognitive Behavioral Therapy (CBT), for the treatment of pain to reduce reliance upon high-dose chronic opioids. CBT can effectively reduce pain without increasing costs or producing debilitating side effects associated with opioid medications. Unfortunately, its use in clinical practice is limited, as most of CBT benefits are believed to be related to the improvement of coping but not to pain modulation itself. We have repeatedly shown that 11 weeks of CBT for pain management can significantly reduce pain, suggesting that CBT could be employed as an adjunct therapy in clinical pain settings. Furthermore, we have recently determined that CBT-related pain relief engages multiple neural mechanisms and increases in cognitive control, emotion regulation, and executive processing. However, it remains unknown if CBT related pain relief activates endogenous opioid systems. Interestingly, we and others found that placebo, meditation and CBT attenuates pain responses by activating brain regions (e.g., anterior cingulate cortex, anterior insula, orbitofrontal cortex) containing high concentrations of opioid receptors. In addition, CBT is postulated to attenuate pain by cognitive control processes and reducing expectations of impending noxious stimuli, mechanisms that are partially mediated by endogenous opioid systems. Therefore, we postulate that CBT engages endogenous opioid systems to reduce pain. This project will incorporate a unique combination of expertise and methodologies to achieve this aim, including a randomized, controlled 11 week CBT intervention, assessment of pre- to post-intervention changes in daily chronic back pain intensity based on telephone-based diaries, and controlled laboratory assessment of pre- to post- intervention changes in endogenous opioid function, tested by effects of opioid blockade on evoked pain responses relative to placebo condition. The proposed experiment will provide novel insight into the mechanisms supporting CBT-related pain relief, thereby providing a foundation for greater use of CBT in clinical settings. Project results would potentially lead to changes in clinical practice with significant population benefits, given the frequency with which chronic opioids are currently used and their recognized negative consequences.